The long term goal of this project is to target and inhibit the receptor for advanced glycation end products (RAGE) signaling in glioblastoma (GBM) utilizing an oncolytic virus (OV) that secretes endogenous secretory RAGE (OVesRAGE), and evaluate the anti-tumor effects, as well as effects on the tumor microenvironment (TME). Knowledge obtained from this project will provide pre-clinical evidence for the use of this novel OV for the treatment of GBM. Discoveries from this project will broaden our understanding of mechanisms that can be utilized to modulate the TME to provide a more favorable response to OV therapy. GBM is a lethal, primary brain tumor diagnosed in adults. Standard of care therapy comprised of surgical resection, radiotherapy, and chemotherapy, provides only a modest increase in overall survival, where most patients succumb to the disease within 18 months of diagnosis. Therefore, there is a dire need for new therapies for the treatment of these patients. RAGE is a transmembrane protein from the immunoglobulin superfamily with multiple splice variants and a secreted variant, esRAGE. Interaction of full length RAGE with its ligands, such as advanced glycation end products (AGEs), High Mobility Group Box protein 1 (HMGB1), or s100 proteins, induces a signaling cascade where NF-?B is activated, promoting inflammation, endothelial cell activation, and angiogenesis. esRAGE lacks the transmembrane domain and cytosolic tail necessary for signal transduction, but rather acts as a decoy upon secretion by competing with full length RAGE for ligands, thus neutralizing RAGE signaling. Furthermore, esRAGE levels in cancer patients have been correlated with a more favorable prognosis and increased overall survival. We have developed an OV derived from the Herpes Simplex Virus-1 (HSV), similar to the FDA approved Talimogene Laherparepvec that secretes esRAGE following GBM cell infection. We hypothesize that modulation of RAGE signaling utilizing esRAGE as a decoy receptor will enhance OV therapy by inhibiting NF-?B activation, and thus decrease endothelial cell activation and macrophage infiltration, allowing for increased viral replication and anti-tumor effects. Ultimately, this therapy will increase overall survival in tumor-bearing mice. Using human and murine models of GBM, we aim to elucidate the effects of RAGE signaling inhibition, via delivery of esRAGE, on the TME and viral replication (Aim 1), and assess the anti-tumor effects of OVesRAGE therapy (Aim 2). Overall, we aim to provide an additional treatment option for GBM patients and provide pre-clinical evidence to demonstrate the feasibility of successful clinical translation.